Nitric oxide (NO) donors are know to be useful for therapeutic utility, e.g., to prevent restenosis following angioplasty (Gloves, P., et al., Cardiovascular Research 26, 615-619 (1992)), to inhibit platelets to prevent coagulation and thrombus formation (Groves, P., et al., Circulation 87, 590-597 (1993)) and to treat angina (Knight, et al., Circulation 95, 125-132 (1997)). NO donors are considered to have additional therapeutic utility in treating cancer, killing microbes and viruses, relaxing airways and intestinal smooth muscle (e.g., for treating asthma and esophageal spasms), in promoting erectile function and in treatment of heart failure and urinary incontinence.
Nitric oxide can exist in three forms, namely in the oxidized form as nitrosonium ion (NO+), as neutral nitric oxide (the stable free radical NO.) and in the reduced form as nitroxyl ion (NO−).
The three forms are considered to have different physiological functions.
Administration of nitrosonium ion is favored for signaling receptors. The C-nitroso compounds that are the subject of the following set of patents where one of the inventors herein is a co-inventor, donate nitric oxide in the form of nitrosonium ion: see U.S. Pat. Nos. 6,359,182; 6,538,116; 6,887,994; 7,030,238 and 7,049,308. These C-nitroso compounds generate nitrosonium instead of nitroxyl because the nitroso is derived from a carbon acid with relatively low pKa so that there is no beta proton acidic enough to cause beta elimination between the nitroso and the beta proton.
Administration of neutral nitric oxide is favored for vasodilation and to inhibit aggregation of platelets.
Administration of nitroxyl ions increases cardiac output and reduces venous output for treatment of heart failure and protects against reperfusion injury.
A compound known to donate nitroxyl ion is Angeli's Salt, which is used to produce nitroxyl ion in situ. Angeli's salt decomposes in water to release nitroxyl and neutral nitric oxide. A problem with Angeli's salt is that it is associated with a single rate of delivery regardless of the rate of delivery required or most beneficial.